1. Field of This Invention
This invention relates to food and feed supplements. More particularly, this invention relates to food and feed supplements which are effective in retarding or delaying many biochemical and sub-cellular reactions ordinarily associated with the biological degradations which are as a group considered to be the aging process. This invention relates to food and feed supplements which prevent and/or retard all types of cancer (including metastasis) by preventing certain types of oxidation and by alteration of enzyme activity and increaed antibody production. Further, this invention relates to food and feed supplements which are effective in preventing or retarding obtrusive lung disease by the protection of lung membranes from pollution. This invention also relates to food and feed supplements which are effective in preventing the occurrence of and/or retarding atherosclerosis, crib death, muscular dystrophy, radiation illness, xeroderma pigmentosum (here the body damage is slowed), etc. A commonality of all of these biological degradations is the integrity of cellular membranes and their topographical and oxidation-reduction relationships. A major function of this invention is to preserve the membranes, reduce attacks on the membrane by the reduction of extraneous free radicals, to speed repair of membranes and to protect the extra and intracellular components. A second feature, common to the protective mechanisms in several of the above degradations, is the reduction of mis-synthesized proteins caused by altered DNA, and the stimulation of antibodies to destroy the mis-synthesized protein or other agents.
2. Related Art
The following references may or may not be prior art to this invention.
Man does not produce the vitamin C which he needs. Stone, Irwin, "Hypoascorbemia, The Genetic Disease Causing The Human Requirement For Exogeneous Ascorbic Acid", Perspectives in Biology and Medicine, Vol. 10, No. 1, (1966); Stone, Irwin, "On The Genetic Etiology of Scurvey", Acta Geneticae Medicae et Gemellologiae, Vol. XV, No. 4, (October 1966).
Biochemical stress causes man to further deplete his ready stores of ascorbic acid. Stone, Irwin, "The Genetic Disease, Hypoascorbemia--A Fresh Approach To An Ancient Disease And Some Of Its Medical Implications", Acta Geneticae Medicae et Gemellologiae, Vol. XVI, No. 1, (January 1967).
The possibility of the use of 25 to 50 grams per day or even higher of ascorbic acid in collogen diseases, such as arthropathies, the rheumatoid diseases and even the aging process, has been suggested. Stone, Irwin, "The Genetic Disease Hypoascorbemia--A Fresh Approach To An Ancient Disease and Some Of Its Medical Implications", Acta Geneticae Medicae at Gemellologiae, Vol. XVI, No. 1, (January 1967).
Stone, Irwin, "The Genetic Disease, Hypoascorbemia", Acta Geneticae Medicae et Gemellologiae, Vol. XVI, No. 1, (January 1967), states much more than one or two grams per day of ascorbic acid would be needed in cancer therapy.
Most daily vitamin dosage levels have been in the milligram range. Some recent sources have recommended large or massive daily dosages of ascorbic levels.
Stone, Irwin, "Hypoascorbemia, The Genetic Disease Causing The Human Requirement For Exogenous Ascorbic Acid", Perspectives In Biology and Medicine, Vol. 10, No. 1, (1966), states that under stress conditions a 70-kg individual would need up to 15.2 grams of ascorbic acid.
Stone, Irwin, "The Genetic Disease, Hypoascorbemia", Acta Geneticae Medicae et Gemelloiogiae, Vol. XVI, No, 1, (January 1967), states that fairly high levels of ascorbic acid should not be toxic.
Rodale, "The Complete Book Of Vitamins", (1966), discloses a 20 percent increase in mouse median life span by adding butylated hydroxytoluene, at the level of 1 to 5 percent of the total diet, to their diet (referring to the work of Harman).
Attention is drawn to: Schwarz, Klaus, "Role Of Vitamin E, Selenium And Related Factors In Experimental Nutritional Liver Diseases", Federation Proceedings, Vol. 24, (January-February 1965), pp. 58 to 64.
Separatum Experientia, 26, 840, (1970), "Vitamin E Deficiency And Chemical Carcinogenesis", states:
"Since vitamin E and intracellular antioxidants are reported to be enriched in tumor tissues as compared to normal tissue, some retardation of tumor induction of tumor growth might be expected in acute vitamin E deficiency. Since the growth of the animals in group 4 was poor, it was difficult to ascribe the decreased size of liver tumors observed in several rats from this group to vitamin E deficiency-alone. Suprisingly, Swick and Bauman have reported that dietary vitamin E decreased the incidence of hepatomas when large amounts of the vitamin were fed after administration of 3-methyl-4-dimethylamino-azo-benzene." PA1 "Miller et al. used a diet containing 0.06% p-dimethyl-aminoazobenzene and low in vitamin E and have concluded that vitamin E does not exert any effect on the carcino-genicity of p-dimethylaminoazobenzene. Since they used relatively larger rats (initial wt. 180 g vs 60 g used in the present experiment) a lower level of fat (5% vs 10%), a much shorter total period of experimentation (6 months vs 18 months),and did not establish the vitamin E deficiency status. However, the present results, obtained with a different carcinogen (FAA) under more controlled conditions are essentially in agreement with their data. Thus it can be stated that vitamin E deficiency, under the present experimental conditions, does not accelerate the induction or growth of tumors by FAA in rats." [Emphasis supplied][col. 2 2nd and 3rd paragraphs] PA1 "The Tulane researchers could not demonstrate significant differences in the 24-hour excretion of 3-HOA by bladder tumor patients, smokers and normal patients who were nonsmokers. But they did find much more cinnabaric acid in urine from the tumor patients. And in all three groups, ascorbic acid prevented the formation of this compound." [at page 63, lines 14 to 20] PA1 "Recently it has been observed that the incidence of mammary carcinoma induced in female white rats by 7,12-dimethyl benz(a) anthracene was higher when the diet contained 20 per cent by weight of corn oil in comparison to the same amount of a saturated fat, coconut oil (31). This result probably is a reflection of a higher rate of lipid peroxidation in the rats fed the corn oil diet, since in a similar experiment in which the base diet was 20 percent by weight of corn oil to which was added either 5 or 20 mg of .alpha.-tocopherol acetate per 100 grams of diet, the rats receiving the vitamin-E supplemental diet had significantly fewer tumors (32)." PA1 (1) Water soluble antioxidant vitamin C, or ascorbic acid, or any of its forms or derivatives, or mixtures thereof; PA1 (2) Oil soluble anitoxidant vitamin E, or alpha-tocopherol, or any of its forms or derivatives, or mixtures thereof; PA1 (3) The element selenium, or a chemical containing it, or mixtures thereof; PA1 (4) A sulfur amino acid, in any form, or a sulfur peptide, or a sulfur protein, or any of their derivatives, or mixtures thereof; and PA1 (5) Another antioxidant, other than vitamin C and other than vitamin E, which is synthetic or natural and water soluble or oil soluble, or a mixture of such antioxidants, or a combination of such forms thereof. PA1 "1) There is not a single published report of experimental evidence which demonstriated that aging is the result of or even accompanied by `protein mis-synthesis.` Coding errors have been reported to occur, but again, there is not the slighest bit of evidence to suggest that such phenomenom is age-dependent." PA1 "2) There also is not a single published report of experimetnal evidence which demonstrated interference of age-dependent deterioration of physiological function following administration of the `drugs` included in Mr. Passwater's [the inventor's] formulation." [at p. 9]
So it is seen that the Separatum Experientia reference discloses that a deficiency of vitamin E does not accelerate the induction of cancer.
Brewer, Keither A., "Excitation Of The Hydrogen Double Bond", American Scientist, Vol. 56, No. 3, at pages 261 and 263, states that cancer can be induced in the skin by exposure to ultraviolet radiation by penetrating radiation and by long exposure to heat. It also states that carcinogens are complex molecules containing benzene rings with substitutions in the meta position and such compounds can be synthesized from polymers upon excitation by heat, UV radiation, x-rays, .alpha., .beta. and .GAMMA. rays and electron bombardments.
Webster, James, "Vitamin C--The Protective Vitamin", Universal-Award House, Inc., (1971), at pages 61 to 64, 154 and 155 deals with vitamin C (ascorbic acid) and cancer. After referring to an article published in the Jun. 21, 1968, issue of "Medical World News", it stated: "*** Dr. *** advised his patients who have had bladder cancer that the trouble may not come back if they take lots of Vitamin C." [Emphasis supplied] [at page 61, last four lines]. Such statement is only speculative as it uses the word "may". It is also noted that such statement only deals with patients using vitamin C after they have already had bladder cancer. The reference quotes: "He prescribes a gram and a half a day to prevent recurrences of carcinomia of the bladder." [at page 62, lines 3 and 4]. Any positive aspects of such statement is eliminated by the following further quotation: "We have enough circumstantial evidence to warrant a trial of ascorbic acid to prevent recurrences". [emphasis supplied] [at page 62, lines 10 and 11] So such statement, at best, is only an invitation to experiment.
The Webster reference, in dealing with the Medical World News article, also quotes:
That is not a statement that large amounts, i.e., 1.5 grams, of ascorbic acid will prevent or cure any type of cancer.
The Webster reference, at page 66 lines 9 to 13, states: "*** the efficiency of Vitamin C *** except for hopeful results concerning bladder cancer."[emphasis supplied] Such statement is only speculative and, at best, an invitation to experiment.
The Webster reference, in dealing with an article by E. Schneider in the A.M.A. Journal, quotes: "`A Vitamin C deficiency varying from 3000 to 9000 mg, with an average defiency of 4550 mg was revealed by serial examination with the saturated method performed on ten patients with carcinoma of the stomach, rectum, and uterine cervix and with bronchial carcinoma. In an attempt at improving the general condition of patients with carcinoma before surgical intervention, this Vitamin C deficiency was compensated by daily administration of 1000 to 2000 mg of Vitamin C. Administration of Vitamin C increases the *** defense power but does not exert any anticancerous effect.`" [at page 154, lines 10 to 20] Such statement only states that the "defense power" whatever that means is increased and does not state that large amounts of vitamin C prevent cancer. The phrase "defense power" most likely applies to the normal body defense mechanisms against colds and normal diseases because of the reference of giving the large amounts of vitamin C in "an attempt at improving the general condition of patients with carcinoma before surgical intervention."
The Webster reference, in continuing on the Scheider article, quotes a passage that states that daily dosages of 1000 mg of vitamin C and large amounts of vitamin A to various cancer patients helped their general condition, prolonged life and temporarily reduced the size of tumors. Whatever that quotation contains, it does not state that large amounts of vitamin C prevent cancer formation. A further quotation summarizes the entire disclosure in perfect fashion: "`Massive vitamin therapy has the advantage od being free of any risk, since it has no component that may potentially influence tumor development.`" [emphasis supplied] [at page 155, lines 20 to 22] That is another way of saying that high dosages of vitamin C or vitamins C and A are not potential means for preventing the development of cancer.
Georgieff, K. K., "Free Radical Inhibitory Effect of Some Anticancer Compounds", Science, Vol. 173, No. 3996, (1971), pp. 537 to 539, was an attempt to determine whether some typical anticancer compounds were also free radical inhibitors that might block biological reactionsinvolving free radicals. The Georgieff reference, in Table I, shows that at least n-propyl gallate, Mitomycin C, hydroxyurea and vitamin A alcohol have higher free radical inhibition factors than does Vitamin C. Copper compounds are also better. Vitamin C is stated to have little or no anti-tumor activity, but it is supposed to potentiate the activity of other anti-cancer compounds. The Georgieff reference states: "Vitamin C ***. *** can act as a reducing agent in redox polymerization systems. Thus, under one set of conditions, L-ascorbic acid can promote the formation of unstable free radicals and under another it can inhibit them. *** Ascorbic acid *** appears to inhibit various tumors. Glycolysis and repiration of the tumor cells are diminished." [at page 539, col. 1, line 21 to 53] Such statement is speculative and shows that known L-ascorbic acid action is confusing and contradictory. The further speculative nature of the Georgieff reference is shown by the following quotation: "Several ubi quitous compounds (copper, vitamins A and C, and ketoaldehydes), which either suppress the growth of cancer or enhance the carcinocidal effect of other anticancer compounds, show substantial free radical inhibition. Many other natural compounds also appear to be free radical inhibitors as a result of their chemical structures. Most synthetic anticancer compounds that I studied displayed significant inhibitory activity. Thus, free radical inhibitors would appear to play some important role in the biochemistry of the normal cell and in the suppression of cancerous growth." [at page 539, col. 2, lines 8 to 23]
The theory behind the speculations in the Georgieff reference is stated to be: "Previous investigators have found that free radicals are formed when living tissue is irradiated with high energy radiation, and when the dose is sufficiently high, carcinogenesis occurs. The host is often protected with free radical scavengers when being treated with radiation. *** the exact role of these free radicals has not yet been established. These observations, as well as those in previous paragraphs, are consistent with the hypothesis that in normal cells there is a balance between unstable free radicals and free radical inhibitors (and their resulting stable free radicals), which probably involves several or many different reactions. An excess of unstable free radicals will tend to induce reactions that will result in carcino-genesis, whereas free radical inhibitors will tend to restore the balance and inhibit cancer. If this hypothesis is correct, the addition of adequate amounts of certain nontoxic free radical inhibitors to the human diet may reduce the incidence of some types of cancer." [emphasis supplied] [at p. 539, col. 2, line 36 to col. 3, line 12]. Even the Georgieff reference states: "Whether my inhibition factors *** have any quantitative significance in biological systems has yet to be established." [at p. 537, col. 2, line 47, to col. 3, line 2)--which suggests the use of very low amounts of free radical inhibitors for biological systems.
Feedstuffs, "The Case For Selenite As A Feed Additive", vol. 43, No. 13, p. 12 et seq., states that Se was long ago alleged to be a possible cause of cancer, but speculates that a deficiency of Se or vitamin E may reduce resistance to carcinogen attack.
Feedstuffs, (Apr. 17, 1971), Letters To The Editor, page 10, First Letter, states "*** Dr. R. J. Shamberger's discovery of inhibition of experimental skin carcinogenesis in mice by simultaneous skin painting with sodium selenide or vitamin E and croton oil ***." It also states that there is an inverse relationship between human cancer mortality and the geographic distribution of Se.
Can. Med. Assoc. J., Vol. 100, (Apr. 12, 1969), Correspondence, page 682, Shamberger Letter, discloses sodium selenide reduced the number of animals with tumors in several carcinogenesis experiments; likewise with animals fed adequate selenium elvels. It also states that there is an inverse relationship between selenium blood levels and human cancer death rates.
The Merck Index, 6th Ed., (1962), page 626, states that methionine is a nutrient, that the recommended daily intake of L-methionine for a normal adult made is 2.2 grams, has been used in fatty infiltration, cirrhosis of the liver and toxic hepatitis, that anorexia nausea and vomiting may occur following large doses, and the oral dosage of DL-methionine was 3 to 6 grams per day.
Chem. & E. News, (Apr. 10, 1972), p. 14, basically teaches that cancer produces or puts out free radicals.
In Harman, Denham, "Free Radical Theory Of Aging: Effect. Of Free Radical Reaction Inhibitors On The Mortality Rate Of Male LAF.sub.2 Mice", J. of Gerontology, Vol. 23, No. 4, (October 1968), at page 478, it was reported that no gross tumors were found in mice during an experimental period in which they were fed a daily diet which contained among other things, 20 mg. of .alpha.-tocopherol acetate.
Chem. & E. News, (Jun. 29, 1970), "Vitamin A And E Help Maintain Lung Health", states that in one study high dosages of vitamin A, given to benzpyrene-treated hamsters, can inhibit completely the appearance of squamous tumors of the lung. Also, in another study, healthy hamsters, which had been given large dosages of vitamin A for 12 days, had benzpyrene-induced anaplastic tumors from the lungs of hamsters transplanted. It was stated that it was not known from those tests whether there might be a change in cell structure and tumor growth rate.
Harman, Denham, "Prolongation Of Life: Role Of Free Radical Reactions In Aging", J. of the American Geriatrics Society, (August 1969), at page 728, treates the subject of cancer in the title area. Harman, at page 728, lines 13 to 21, states:
It is noted that the quotation is directed to showing that a corn oil diet is probably the key to the lowering of the occurrence of tumors and mammary carcinoma.
Mirvish, Sidney S., et al., "Ascorbate-Nitrate Reaction: Possible Means Of Blocking The Formation Of Carcinogenic N-Nitroso Compounds", Science, Vol. 177, (Jul. 7, 1972), at pages 65 to 68, presents chemical data that shows that ascorbic acid blocks the formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and compounds like piperazine. Urea and ammonium sulfamate were less effective blocking agents. The article suggested the possibility of in vivo formation of carcino-genic N-nitroso compounds from drugs could be lessened by the combination of such drugs with ascorbic acid. The article states "that ascorbic acid might be used for this purpose." [Emphasis supplied].
Most animals synthesize enough vitamin C for their need, but man and other primates do not have the capacity to synthesize vitamin C.
Attention is drawn to: "Symposium Proceedings--The Bio-chemistry, Assay And Nutritional Value Of Vitamin E", Association of Vitamin Chemists, (Mar. 27, 1969); Chem. & E. News, (Aug. 17, 1970), p. 31; Chem. & E. News, (Jun. 29, 1970), pp. 38 and 39; Science, Vol. 169, No. 3945, (Aug. 7, 1970), pp. 605 & 606; Frost Douglas V., Feedstuffs, (Jul. 31, 1971), pp. 11 et seq.; Scott, M. L., International Journal for Vitamin Research, Vol 40, No. 3, (1970), pp. 334 to 343; Chem. & E. News, (Sep. 11, 1972), p. 22; Prevention, (December 1971), pp. 104 to 110; Shamberger, Raymond J., et al., Cleveland Clinic Quarterly, Vol. 39, No. 3, (1972), pp. 119 to 124; Shamberger, Raymond J., Journal of The National Cancer Institute, Vol. 48, No. 5, (May 1972), pp. 1491 to 1497;and Shamberger, Raymond J., Journal Of The National Cancer Institute, Vol. 44, No. 4, (April 1970), pp. 931 to 936.
The convenient preparation of dimethyl selenide is mentioned by Bird and Challenger in "Potassium Alkaneselenonates and Other Alkyl Derivatives of Selenium" in the Journal of the Chemical Society (London) (1942) pages 570 to 572.
The toxicity of dimethyl selenide was investigated by McConnell and Portman and reported in "Toxicity of Dimethyl Selenide in the Rat and Mouse" in the Proceedings of the Society for Experimental Biology and Medicine, Vol. 79 (1952) pages 230 and 231. They found dimethyl selenide to be several hundred times less toxic than all other forms of selenium tested for toxicity, except elemental selenium.
Since the 1942 preparation and 1952 toxicity reports, there does not appear to have been any further investigation of dimethyl selenide for use in man or animal, for any purpose. Nor does there appear to be any suggestion by anyone for further investigation of the use of dimethyl selenide for any purpose. All other known references to dimethyl selenide are as a metabolic product of some other form of selenium. Dimethyl selenoxide, the first oxidation product of dimethyl selenide, would be similar in structure to dimethyl sulfoxide (DMSO), a chemical which has caused considerable controversy.